Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. The name “Wnt” was coined as a combination of Wg (wingless) and Int. The wingless gene had originally been identified as a segment polarity gene in Drosophila melanogaster that functions during embryogenesis, and also during adult limb formation during metamorphosis. The Int genes were originally identified as vertebrate genes near several integration sites of mouse mammary tumor virus (MMTV). The Int-1 gene and the wingless gene were found to be homologous, with a common evolutionary origin evidenced by similar amino acid sequences of their encoded proteins.
Many Wnt genes in the mouse have been mutated, leading to very specific developmental defects. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to β-catenin, which then enters the nucleus and forms a complex with TCF (T Cell Factor) to activate transcription of Wnt target genes.
Wnt genes and Wnt signaling also have been implicated in cancer. Autocrine Wnt signaling within tumor cells has been shown to promote tumorigenesis by enhancing tumor cell proliferation and survival. The deregulation of this pathway can be detected in numerous cancers, resulting in the accumulation of beta-catenin (β-catenin) in the cell nucleus where it interacts with transcription factors of the LEF/TCF family and induces transcription of wnt target genes. There is mounting evidence of Wnt pathway activation during prostate tumorigenesis. Further, beta-catenin functions as a coactivator for the androgen receptor. The frequent dysregulation of wnt in prostate cancers suggests that this pathway is suitable for therapeutic intervention.
Current therapy for advanced prostate cancer relies on traditional cytotoxic agents with limited effects. This has spurred an increased interest in understanding the mechanisms of prostate cancer tumorigenesis at the molecular level with the aim of finding specific molecular targets for intervention. Abnormal Wnt signaling in the development and progression of human prostate cancer has been demonstrated and the molecular details of various aberrant feed back mechanisms are being elucidated. From these investigations, including the accumulation of beta-catenin in the cancer cell nucleus, its complexation with the TcF family transcription factors to activate a variety of cancer-associated genes, Wnt has been associated with tumor progression, including metastatic lesions of the bone. Compounds that disrupt this path at the transcription level are being sought for the development of new products for therapeutic use.